Persistence and proliferation of human mesenchymal stromal cells in the right ventricular myocardium after intracoronary injection in a large animal model of pulmonary hypertension

Abstract

Background aims In this study, we demonstrate long-term persistence of human mesenchymal stromal cells (hMSCs) after intracoronary injection in a large animal model of pulmonary hypertension (PH). Methods Commercially available placenta-derived hMSCs were used. Experiments were conducted on 14 female Yorkshire swine. Four animals served as controls, and 10 underwent pulmonary vein (PV) banding. After 12 ± 2 weeks, PH and PV dysfunction were confirmed by right heart catheterization and cardiac magnetic resonance imaging. hMSCs were injected in the marginal branch of the right coronary artery. Tissues were harvested 6, 9 or 24 days after infusion. Results After 12 ± 2 weeks after PV banding, all subjects had increased mean pulmonary artery pressure (13.6 ± 3.6 versus 30.8 ± 4.5 mm Hg, P < 0.007) and a decrease in right ventricular ejection fraction from 51.7 ± 5.7% versus 30.5 ± 11.3% (P = 0.003). Intracoronary injection of hMSCs was well tolerated. Up to 24 days after hMSC injection, immunohistochemistry revealed extravascular viable human CD105+ mononuclear cells in the right ventricle (RV) that were Ki67+. This was confirmed by fluorescence in situ hybridization. CD45+ porcine inflammatory cells were identified, commonly seen adjacent to areas of healing microscopic infarction that likely dated to the time of the original hMSC injection. Anti-CD31 staining produced strong signals in areas of injected hMSCs. Immunohistochemistry staining for vascular cell adhesion molecule-1 showed upregulation in the clusters, where mononuclear cells were located. Conclusions hMSCs injected via intracoronary infusion survived up to 24 days and demonstrated proliferative capacity. hMSCs can persist long term in the RV and are potential cell source for tissue repair in RV dysfunction.

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

“…Pulmonary arterial hypertension (PAH) is a chronic and devastating disease in which extensive obliterative changes are associated with elevated pulmonary arteries pressure, pulmonary vascular resistance, and right ventricular (RV) dysfunction, resulting in vascular fibrosis and stiffening [108,109]. Mounting evidence has shown that treatment with rat MSC or human MSC treatment is able to decrease pulmonary vascular resistance, improve vascular endothelial function and right ventricular function in the monocrotaline or Su5416/hypoxia-injured lung [110][111][112][113] through regulating [Ca 2+ ]i signal-associated cellular behaviours [114], normalizing the expression levels of apoptosis (active-caspase-3), cellular proliferation (p-38 MAPK and ERK5), and inflammation markers (TNF-α, IL-1β, IL-6) [115], suppressing TLR-4 signalling [116], expressing Heme Oxygenase-1 (HO-1), enhancing let-7a expression [117], and dampening endothelialmesenchymal transition (EndMT) [118,119]. Moreover, high throughput sequencing has demonstrated that six miRNAs of MSCs (upregulated: miR573 and miR1246; downregulated: miR206, miR-133a-3p, miR-141-3p and miR-200a-3p) are differentially expressed with co-culturing with human pulmonary arterial endothelial cells (HPAECs) [120].…”

Wnt/β-Catenin Participates in the Repair of Acute Respiratory Distress Syndrome-Associated Early Pulmonary Fibrosis via Mesenchymal Stem Cell Microvesicles

“… 34 , 35 Over the past few decades, MSCs, regarded as “the next pillar of medicine” have been shown to successfully reduce inflammatory response and collagen deposition, 36 reduce pulmonary vascular resistance, and improve vascular endothelial function and appropriate ventricular function in a bleomycin-induced model of lung injury. 37 , 38 Recent studies support the utility of MSC therapy as a potential option for treating cases of severe ARDS and cytokine storm resulting from the novel coronavirus disease COVID-19, although preclinical data are current lacking. 39 However, existing data suggests that only a small number of MSCs are capable of preferentially targeting damaged regions and surviving for over 24 h following systematic administration.…”

Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

“…It is also important to address that hMSCs can persist long-term in the RV by intracoronary injection and are a potential cell source for tissue repair in RV dysfunction induced in a large animal model of pulmonary hypertension (Badr Eslam et al, 2017). Herein, we expanded these beneficial findings on hMSCs for the whole cardiopulmonary system, now in a suitable rodent model of PAH.…”